The Sloan-Kettering Institute requests a high resolution/high mass accuracy time-of-flight mass spectrometer with an ultra high performance liquid chromatography front end (LC-TOF-MS). This instrument will be used by synthetic chemists who are developing new biological probes and therapeutic agents targeted to cancer, infectious diseases, and neurodegenerative disorders. Sloan-Kettering has a well-established and expanding chemistry program, but these chemists do not have on-site access to a high resolution mass spectrometer. As a result, samples are currently shipped to external service facilities with long turnaround times (up to 28 days), which delays research progress and is not feasible for samples that are prone to decomposition. Furthermore, experiments that benefit from LC-HRMS, such as identification of unknown components in mixtures, are not currently feasible. The requested instrument provides high sensitivity, simultaneous APCI and ESI ionization, fast positive/negative ion mode switching, fast scan rate, wide dynamic range, and full integration with ultra-HPLC separation of individual sample components. On-site access to this new instrument will provide these critical capabilities to chemists at Sloan-Kettering on a routine and cost- effective basis. NIH-supported users include (1) Dr. Samuel Danishefsky, who is synthesizing natural products and glycopeptide vaccines with anti-tumor and anti-infective properties, several of which have been advanced to human clinical trials; (2) Dr. Gabriela Chiosis, who is developing modulators of the chaperones Hsp70 and Hsp90 to investigate their therapeutic potential; (3) Dr. Yueming Li, who is studying ?-secretase function and inhibition to target Alzheimer's disease; (4) Dr. Bayard Clarkson, who is investigating kinase inhibitors as new treatments for chronic myeloid leukemia; (5) Dr. Derek Tan, who is developing diversity-oriented syntheses of natural product-based libraries for high-throughput screening against a broad range of biological targets and also developing new antibiotics targeting siderophore biosynthesis in pathogenic bacteria; (6) Dr. Steven Larson, who is developing new radiotracers for biochemical and metabolic studies to diagnose and treat cancer; and (7) Dr. Ouathek Ouerfelli, whose Organic Synthesis Core Facility provides chemistry services to more than 20 other NIH-supported investigators at Sloan-Kettering. The LC-TOF-MS instrument will be located in the Sloan-Kettering Analytical NMR Core Facility, which currently provides low resolution mass spectrometry services to these chemists, and managed by Dr. George Sukenick, who has 13 years of experience in directing this facility. Public Health Relevance Statement: The requested instrument will be used by chemists at the Sloan- Kettering Institute to characterize synthetic molecules. The new capabilities provided by this instrument will greatly accelerate and assist their efforts to develop new biological tools and therapeutic agents to study and treat cancer, infectious diseases, and neurodegenerative disorders. [unreadable] [unreadable] [unreadable]